DESCRIPTION: Major Depressive Disorder (MDD) has become one of the most pressing health-related problems in the United States. While there appears to be numerous etiologies for MDD, social bond disruption and early-life stress are two of the most commonly cited risk factors. Unfortunately, the consequences of social bond disruption on the mental state are difficult to study in traditional laboratory animal models. Furthermore, current animal models provide little insight into how early-life stress influences the prosocial brain. Monogamous prairie voles offer a novel animal model for investigating the convergence of these two factors in the development of depression at both the behavioral and neurobiological levels. Male prairie voles separated from their female partner display depressive-like behavior and an activation of the stress axis. The increase in depressive-like behavior following social loss appears to be mediated by the corticotropin-releasing factor (CRF) system, as blocking either of the CRF receptors (CRF1 or CRF2) prevents the onset of depressive-like behavior following social loss. Interestingly, monogamous prairie voles and non-monogamous meadow voles exhibit species differences in CRF1 and CRF2 in the brain, particularly in the nucleus accumbens (NAcc) Activation of CRF1 and CRF2 in the NAcc facilitates pair bond formation, and pair bonding results in increased CRF mRNA in the bed nucleus of the stria terminalis (BnST). These data have led to the hypothesis that activation of CRF receptors in the NAcc of male prairie voles also plays an important role in the emergence of depressive-like behavior following separation from the partner. In this proposal, a pharmacological approach will be used to determine whether CRF receptors in the NAcc are responsible for social loss-induced depressive-like behavior. Viral vector mediated siRNA silencing will be used to determine whether CRF expressing neurons in the BnST regulate the onset of depressive-like behavior following social loss. Finally the influence of early-life social experience and adversity on the CRF system and the behavioral response to social loss will be examined in prairie voles. These studies will provide a deeper understanding of how social loss and early life stress impact the brain mechanisms underlying major depression. PUBLIC HEALTH RELEVANCE Major depression is one of the most debilitating psychiatric disorders and most burdensome diseases to society, with as many as 30 million Americans affected. Social bond disruption and early-life stressors have a major impact on the likelihood of developing depression. The studies in this proposal will investigate the interaction of social bond disruption and early-life stressors on the brain mechanism underlying depressive-like behavior in an animal model.